Lipid-Conjugated\nReduced Haloperidol in Association\nwith Glucose-Based Nanospheres: A Strategy for Glioma Treatment

Aggressive glioma exhibits a poor survival rate. Increased\ntumor\naggression is linked to both tumor cells and tumor-associated macrophages\n(TAMs), which induce pro-aggression, invasion, and metastasis. Imperatively,\nfor effective treatment, it is important to target both glioma cells\nand TAMs. Haloperidol, a neuropsychotic drug, avidly targets the sigma\nreceptor (SR), which is expressed in higher levels in both the cell\ntypes. Herein, we present the development of a novel cationic lipid-conjugated\nreduced haloperidol (±RHPC8), which aims to mediate the SR-targeted\nantiglioma effect. Hypothetically, ±RHPC8 would act simultaneously\nas an SR-targeting ligand and anticancer agent. As the blood–brain\nbarrier (BBB) obstructs direct targeting of in situ glioma, we used\nBBB-crossing glucose-based carbon nanospheres (CSPs) to deliver ±RHPC8\nwithin the glioma tumor-bearing mouse brain. The resultant ±RHPC8-CSP\nnanoconjugate targeted SR-expressing glioma cells. In both orthotopic\nand subcutaneous mouse tumor models, ±RHPC8-CSP prolonged survival\nand regressed tumors compared to other treated groups. Notably, ±RHPC8-CSP\nwas significantly taken up by SR-expressing TAMs thus resulting in\nmacrophage polarization from M2 to M1, as exhibited by markedly reduced\nexpression of immunosuppressive cytokines released by TAMs, including\nTGF-β, IL-10, and VEGF. In conclusion, the designed ±RHPC8-CSP\nnanoconjugate presented an effective nanodrug delivery system for\nbrain cancer treatment.